Evidence of the effect of dipyrone on the central nervous system as a determinant of delayed gastric emptying observed in rats after its administration

Dipyrone administered intravenously (iv) delays gastric emptying (GE) in rats. The objectives of the present study were to assess: 1) the effect of the dose of dipyrone and time after its iv administration on GE in rats, 2) the effect of subdiaphragmatic vagotomy (VgX) and bilateral electrolytic lesion of the paraventricular nucleus (PVNX) on the delayed GE induced by the drug, and 3) the intracerebroventricular (icv) action of dipyrone and of one of its metabolites, 4-aminoantipyrine on GE. Male Wistar rats received saline labeled with phenol red intragastrically as a test meal. GE was indirectly assessed by the determination of percent gastric retention (GR) of the test meal 10 min after administration by gavage. Dipyrone delays GE in a dose- and time-dependent manner. Thirty minutes after the iv administration of 80 mg/kg dipyrone, the animals showed significantly higher GR (mean = 62.6%) compared to those receiving vehicle (31.5%). VgX and PVNX significantly reduced the iv effect of 80 mg/kg dipyrone (mean %GR: VgX = 28.3 vs Sham = 55.5 and PVNX = 34.5 vs Sham = 52.2). Icv administration of 4 µmol dipyrone caused a significant increase in GR (54.1%) of the test meal 10 min later, whereas administration of 4 µmol 4-aminoantipyrine had no effect (34.4%). Although the dipyrone dose administered icv was 16 times lower than that applied iv, for the same time of action (10 min), the GR of animals that received the drug icv (54.1%) or iv (54.5%) did not differ significantly. In conclusion, the present results suggest that the effect of dipyrone in delaying GE is due to the action of the drug on the central nervous system, with the participation of the PVN and of the vagus nerve.

Hereditary motor and autonomic neuronopathy 1 maps to chromosome 20q13.2-13.3

The spinal muscular atrophies (SMA) or hereditary motor neuronopathies result from the continuous degeneration and death of spinal cord lower motor neurons, leading to progressive muscular weakness and atrophy. We describe a large Brazilian family exhibiting an extremely rare, late-onset, dominant, proximal, and progressive SMA accompanied by very unusual manifestations, such as an abnormal sweating pattern, and gastrointestinal and sexual dysfunctions, suggesting concomitant involvement of the autonomic nervous system. We propose a new disease category for this disorder, `hereditary motor and autonomic neuronopathy', and attribute the term, `survival of motor and autonomic neurons 1' (SMAN1) to the respective locus that was mapped to a 14.5 cM region on chromosome 20q13.2-13.3 by genetic linkage analysis and haplotype studies using microsatellite polymorphic markers. This locus lies between markers D20S120 and D20S173 showing a maximum LOD score of 4.6 at D20S171, defining a region with 33 known genes, including several potential candidates. Identifying the SMAN1 gene should not only improve our understanding of the molecular mechanisms underlying lower motor neuron diseases but also help to clarify the relationship between motor and autonomic neurons.

Effects of caffeine on the electrophysiological, cognitive and motor responses of the central nervous system

Caffeine is the most consumed psychoactive substance in the world. The effects of caffeine have been studied using cognitive and motor measures, quantitative electroencephalography (qEEG) and event-related potentials. However, these methods are not usually employed in combination, a fact that impairs the interpretation of the results. The objective of the present study was to analyze changes in electrophysiological, cognitive and motor variables with the ingestion of caffeine, and to relate central to peripheral responses. For this purpose we recorded event-related potentials and eyes-closed, resting EEG, applied the Stroop test, and measured reaction time. Fifteen volunteers took caffeine (400 mg) or placebo in a randomized, crossover, double-blind design. A significant reduction of alpha absolute power over the entire scalp and of P300 latency at the Fz electrode were observed after caffeine ingestion. These results are consistent with a stimulatory effect of caffeine, although there was no change in the attention (Stroop) test or in reaction time. The qEEG seems to be the most sensitive index of the changes produced by caffeine in the central nervous system since it proved to be capable of detecting changes that were not evident in the tests of cognitive or motor performance.

Effects of age and physical activity on the autonomic control of heart rate in healthy men

The effects of the aging process and an active life-style on the autonomic control of heart rate (HR) were investigated in nine young sedentary (YS, 23 ± 2.4 years), 16 young active (YA, 22 ± 2.1 years), 8 older sedentary (OS, 63 ± 2.4 years) and 8 older active (OA, 61 ± 1.1 years) healthy men. Electrocardiogram was continuously recorded for 15 min at rest and for 4 min in the deep breathing test, with a breath rate of 5 to 6 cycles/min in the supine position. Resting HR and RR intervals were analyzed by time (RMSSD index) and frequency domain methods. The power spectral components are reported in normalized units (nu) at low (LF) and high (HF) frequency, and as the LF/HF ratio. The deep breathing test was analyzed by the respiratory sinus arrhythmia indices: expiration/inspiration ratio (E/I) and inspiration-expiration difference (deltaIE). The active groups had lower HR and higher RMSSD index than the sedentary groups (life-style condition: sedentary vs active, P < 0.05). The older groups showed lower HFnu, higher LFnu and higher LF/HF ratio than the young groups (aging effect: young vs older, P < 0.05). The OS group had a lower E/I ratio (1.16) and deltaIE (9.7 bpm) than the other groups studied (YS: 1.38, 22.4 bpm; YA: 1.40, 21.3 bpm; OA: 1.38, 18.5 bpm). The interaction between aging and life-style effects had a P < 0.05. These results suggest that aging reduces HR variability. However, regular physical activity positively affects vagal activity on the heart and consequently attenuates the effects of aging in the autonomic control of HR.

The inhibitory role of sympathetic nervous system in the Ca2+-dependent proteolysis of skeletal muscle

Mammalian cells contain several proteolytic systems to carry out the degradative processes and complex regulatory mechanisms to prevent excessive protein breakdown. Among these systems, the Ca2+-activated proteolytic system involves the cysteine proteases denoted calpains, and their inhibitor, calpastatin. Despite the rapid progress in molecular research on calpains and calpastatin, the physiological role and regulatory mechanisms of these proteins remain obscure. Interest in the adrenergic effect on Ca2+-dependent proteolysis has been stimulated by the finding that the administration of β2-agonists induces muscle hypertrophy and prevents the loss of muscle mass in a variety of pathologic conditions in which calpains are activated. This review summarizes evidence indicating that the sympathetic nervous system produces anabolic, protein-sparing effects on skeletal muscle protein metabolism. Studies are reviewed, which indicate that epinephrine secreted by the adrenal medulla and norepinephrine released from adrenergic terminals have inhibitory effects on Ca2+-dependent protein degradation, mainly in oxidative muscles, by increasing calpastatin levels. Evidence is also presented that this antiproteolytic effect, which occurs under both basal conditions and in stress situations, seems to be mediated by β2- and β3-adrenoceptors and cAMP-dependent pathways. The understanding of the precise mechanisms by which catecholamines promote muscle anabolic effects may have therapeutic value for the treatment of muscle-wasting conditions and may enhance muscle growth in farm species for economic and nutritional purposes.

Circadian cardiac autonomic function in perinatally HIV-infected preschool children

The 24-h heart rate variability and QT-interval adaptation was investigated in perinatally HIV-infected preschool children classified according to immunological status in order to assess autonomic function at early stages of infection. Thirty-five perinatally HIV-infected and clinically stable children (4.8 ± 0.3 years) were enrolled after approval of the study by the University Hospital Pedro Ernesto Ethics Committee and written informed parental consent was obtained. The children were classified according to peripheral CD4+ count (cells/µL) as follows: group 1, N = 11 (≥1000); group 2, N = 7 (≥500 and <1000); group 3, N = 17 (<500). Left ventricular ejection fraction (>55%), 24-h RR interval variability (RRV) indexes (NN, SDANN, SDNN index, r-MSSD) and 24-h QT and Bazett-corrected QT (QTc) were determined, and groups were matched for age, body surface area, and left ventricular ejection fraction, reducing biases in RRV. The peak differences (∆) between the highest and lowest RRV and QT indexes were extracted from nocturnal (1 am-6 am) and daytime (1 pm-6 pm) hourly assessed segments, respectively. Pearson’s correlation (r) and Kruskal-Wallis ANOVA were used to compare groups. CD4+ count correlated positively with ∆NN (r = 0.45; P = 0.003). There were no significant differences in daytime NN among groups. Nighttime SDNN index (P = 0.01), nighttime r-MSSD (P = 0.003), ∆NN (P = 0.01), ∆SDNN index (P = 0.03) and ∆r-MSSD (P = 0.004) were significantly lower in group 3 than in the other groups. Expected nighttime QTc-interval lengthening was not observed in all groups. In perinatally HIV-infected preschool children with preserved left ventricular systolic function, parasympathetic-mediated autonomic dysfunction parallels immune status, impairing both RRV and circadian QTc interval adaptation.

Autonomic control of cardiorespiratory interactions in fish, amphibians and reptiles

Control of the heart rate and cardiorespiratory interactions (CRI) is predominantly parasympathetic in all jawed vertebrates, with the sympathetic nervous system having some influence in tetrapods. Respiratory sinus arrhythmia (RSA) has been described as a solely mammalian phenomenon but respiration-related beat-to-beat control of the heart has been described in fish and reptiles. Though they are both important, the relative roles of feed-forward central control and peripheral reflexes in generating CRI vary between groups of fishes and probably between other vertebrates. CRI may relate to two locations for the vagal preganglionic neurons (VPN) and in particular cardiac VPN in the brainstem. This has been described in representatives from all vertebrate groups, though the proportion in each location is variable. Air-breathing fishes, amphibians and reptiles breathe discontinuously and the onset of a bout of breathing is characteristically accompanied by an immediate increase in heart rate plus, in the latter two groups, a left-right shunting of blood through the pulmonary circuit. Both the increase in heart rate and opening of a sphincter on the pulmonary artery are due to withdrawal of vagal tone. An increase in heart rate following a meal in snakes is related to withdrawal of vagal tone plus a non-adrenergic-non-cholinergic effect that may be due to humoral factors released by the gut. Histamine is one candidate for this role.

Effect of carotid and aortic baroreceptors on cardiopulmonary reflex: the role of autonomic function

We determined the sympathetic and parasympathetic control of heart rate (HR) and the sensitivity of the cardiopulmonary receptors after selective carotid and aortic denervation. We also investigated the participation of the autonomic nervous system in the Bezold-Jarish reflex after selective removal of aortic and carotid baroreceptors. Male Wistar rats (220-270 g) were divided into three groups: control (CG, N = 8), aortic denervation (AG, N = 5) and carotid denervation (CAG, N = 9). AG animals presented increased arterial pressure (12%) and HR (11%) compared with CG, while CAG animals presented a reduction in arterial pressure (16%) and unchanged HR compared with CG. The sequential blockade of autonomic effects by atropine and propranolol indicated a reduction in vagal function in CAG (a 50 and 62% reduction in vagal effect and tonus, respectively) while AG showed an increase of more than 100% in sympathetic control of HR. The Bezold-Jarish reflex was evaluated using serotonin, which induced increased bradycardia and hypotension in AG and CAG, suggesting that the sensitivity of the cardiopulmonary reflex is augmented after selective denervation. Atropine administration abolished the bradycardic responses induced by serotonin in all groups; however, the hypotensive response was still increased in AG. Although the responses after atropine were lower than the responses before the drug, indicating a reduction in vagal outflow after selective denervation, our data suggest that both denervation procedures are associated with an increase in sympathetic modulation of the vessels, indicating that the sensitivity of the cardiopulmonary receptors was modulated by baroreceptor fibers.

Increased levels of glutamate in the central nervous system are associated with behavioral symptoms in experimental malaria

Cerebral malaria (CM) is a severe complication resulting from Plasmodium falciparum infection. This condition has been associated with cognitive, behavioral and motor dysfunctions, seizures and coma. The underlying mechanisms of CM are incompletely understood. Glutamate and other metabolites such as lactate have been implicated in its pathogenesis. In the present study, we investigated the involvement of glutamate in the behavioral symptoms of CM. Seventeen female C57BL/6 mice (20-25 g) aged 6-8 weeks were infected with P. berghei ANKA by the intraperitoneal route using a standardized inoculation of 10(6) parasitized red blood cells suspended in 0.2 mL PBS. Control animals (N = 17) received the same volume of PBS. Behavioral and neurological symptoms were analyzed by the SmithKline/Harwell/Imperial College/Royal Hospital/Phenotype Assessment (SHIRPA) battery. Glutamate release was measured in the cerebral cortex and cerebrospinal fluid of infected and control mice by fluorimetric assay. All functional categories of the SHIRPA battery were significantly altered in the infected mice at 6 days post-infection (dpi) (P ≤ 0.05). In parallel to CM symptoms, we found a significant increase in glutamate levels in the cerebral cortex (mean ± SEM; control: 11.62 ± 0.90 nmol/mg protein; infected at 3 dpi: 10.36 ± 1.17 nmol/mg protein; infected at 6 dpi: 26.65 ± 0.73 nmol/mg protein; with EGTA, control: 5.60 ± 1.92 nmol/mg protein; infected at 3 dpi: 6.24 ± 1.87 nmol/mg protein; infected at 6 dpi: 14.14 ± 0.84 nmol/mg protein) and in the cerebrospinal fluid (control: 128 ± 51.23 pmol/mg protein; infected: 301.4 ± 22.52 pmol/mg protein) of infected mice (P ≤ 0.05). These findings suggest a role of glutamate in the central nervous system dysfunction found in CM.

Spectral and symbolic analysis of the effect of gender and postural change on cardiac autonomic modulation in healthy elderly subjects

The objective of this study was to use linear and non-linear methods to investigate cardiac autonomic modulation in healthy elderly men and women in response to a postural change from the supine to the standing position. Fourteen men (66.1 ± 3.5 years) and 10 women (65.3 ± 3.3 years) were evaluated. Beat-to-beat heart rate was recorded in the supine and standing positions. Heart rate variability was studied by spectral analysis, including both low (LFnu-cardiac sympathetic modulation (CSM) indicator) and high (HFnu-cardiac vagal modulation (CVM) indicator) frequencies in normalized units as well as the low frequency/high frequency (LF/HF) ratio. Symbolic analysis was performed using the following indexes: 0V% (CSM indicator), 1V% (CSM and CVM indicators), 2LV% (predominantly CVM indicator) and 2ULV% (CVM indicator). Shannon entropy was also calculated. Men presented higher LFnu and LF/HF ratio and lower HFnu and 1V% symbolic index (57.56, 4.14, 40.53, 45.96, respectively) than women (24.60, 0.45, 72.47, 52.69, respectively) in the supine position. Shannon entropy was higher among men (3.53) than among women (3.33) in the standing position, and also increased according to postural change in men (3.25; 3.53). During postural change, the LFnu (24.60; 49.85) and LF/HF ratio (0.45; 1.72) increased, with a concomitant decrease in HFnu (72.47; 47.56) and 2LV% (14.10; 6.95) in women. Women presented increased CSM in response to postural change and had higher CVM and lower CSM than men in the supine position. In conclusion, women in the age range studied presented a more appropriate response to a postural change than men, suggesting that cardiac autonomic modulation may be better preserved in women than in men.

Cardiac autonomic modulation during progressive upper limb exercise by patients with coronary artery disease

The purpose of this study was to investigate the behavior of heart rate (HR) and HR variability (HRV) during different loads of resistance exercise (incline bench press) in patients with coronary artery disease (CAD) and healthy sedentary controls. Ten healthy men (65 ± 1.2 years, control group, CG) and 10 men with clinically stable CAD (66 ± 2.4 years, CADG) were recruited. A discontinuous progressive protocol was applied with an initial load of 10% of the maximum load achieved in the 1RM (1 repetition maximum) with increases of 10% until 30% 1RM was reached, which was followed by subsequent increases of 5% 1RM until exhaustion. HRV was analyzed by linear and non-linear methods. There was a significant reduction in rMSSD (CG: 20 ± 2 to 11 ± 3 ms; CADG: 19 ± 3 to 9 ± 1 ms) and SD1 indexes (CG: 14 ± 2 to 8 ± 1 ms; CADG: 14 ± 2 to 7 ± 1 ms). An increase in HR (CG: 69 ± 5 to 90 ± 5 bpm; CADG: 62 ± 4 to 75 ± 4 bpm) and in systolic blood pressure (CG: 124 ± 3 to 138 ± 3 mmHg; CADG: 122 ± 6 to 126 ± 9 bpm) were observed (P < 0.05) when comparing pre-effort rest and 40% 1RM in both groups. Furthermore, an increase in RMSM index was also observed (CG: 28 ± 3 to 45 ± 9 ms; CADG: 22 ± 2 to 79 ± 33 ms), with higher values in CADG. We conclude that loads up to 30% 1RM during incline bench press result in depressed vagal modulation in both groups, although only stable CAD patients presented sympathetic overactivity at 20% 1RM upper limb exercise.

Presence of central nervous system tissues as bovine spongiform encephalopathy specified risk material in Turkish raw meat ball (cig kofte)

Abstract Bovine Spongiform Encephalopathy (BSE) is a virulent disease which may infect by affecting the central nervous system (CNS) tissues in cattle and causes degeneration in nerves. Central nervous system tissues such as brain and spinal cord which are classified as specified risk materials (SRMs) are regarded to be main source of infection. The contamination of the meat with the specific risk materials (SRMs) can occur in phases of slaughter, fragmentation of carcass and processing. This study was conducted in order to investigate the existence of CNS tissues in raw meat ball (cig kofte) which is commonly consumed in the Southeastern Region of Turkey, particularly in Şanlıurfa. For this purpose, 145 samples of raw meat ball were tested. The enzyme-linked immunosorbent assay (ELISA) kits (Ridascreen risk material 10/5, R-biofarm GmbH) which determine glial fibrillary acidic protein (GFAP) as determinant were used. As a result of the analyses, positivity was detected in 21 of totally 145 samples of raw meat ball (14.48%). 6 (4.14%) of the samples gave low level of positivity (≥ 0.1 standard absorbance), 10 (6.90%) gave medium level of positivity (>0.2 standard absorbance) and 5 (3.45%) gave high level of positivity (≥0.5 standard absorbance). As a consequence, meats are contaminated in any phase of both slaughter and meat production even if accidentally. Regarding this matter, necessary measures should be taken and hygiene rules should be applied.

Depressed cardiac autonomic modulation in patients with chronic kidney disease

Introduction: A dysfunctional autonomic nervous system (ANS) has also been recognized as an important mechanism contributing to the poor outcome in CKD patients, with several studies reporting a reduction in heart rate variability (HRV). Objective: Evaluate the sympathovagal balance in patients with chronic kidney disease on conservative treatment. Methods: In a cross-sectional study, patients with CKD stages 3, 4 and 5 not yet on dialysis (CKD group) and age-matched healthy subjects (CON group) underwent continuous heart rate recording during two twenty-minute periods in the supine position (pre-inclined), followed by passive postural inclination at 70° (inclined period). Power spectral analysis of the heart rate variability was used to assess the normalized low frequency (LFnu), indicative of sympathetic activity, and the normalized high frequency (HFnu), indicative of parasympathetic activity. The LFnu/HFnu ratio represented sympathovagal balance. Results: After tilting, CKD patients had lower sympathetic activity, higher parasympathetic activity, and lower sympathovagal balance than patients in the CON group. Compared to patients in stage 3, patients in stage 5 had a lower LFnu/HFnu ratio, suggesting a more pronounced impairment of sympathovagal balance as the disease progresses. Conclusion: CKD patients not yet on dialysis have reduced HRV, indicating cardiac autonomic dysfunction early in the course of CKD.

Cortical and autonomic modulation of attentional control /

Whereas the role of the anterior cingulate cortex (ACC) in cognitive control has received considerable attention, much less work has been done on the role of the ACC in autonomic regulation. Its connections through the vagus nerve to the sinoatrial node of the heart are thought to exert modulatory control over cardiovascular arousal. Therefore, ACC is not only responsible for the implementation of cognitive control, but also for the dynamic regulation of cardiovascular activity that characterizes healthy heart rate and adaptive behaviour. However, cognitive control and autonomic regulation are rarely examined together. Moreover, those studies that have examined the role of phasic vagal cardiac control in conjunction with cognitive performance have produced mixed results, finding relations for specific age groups and types of tasks but not consistently. So, while autonomic regulatory control appears to support effective cognitive performance under some conditions, it is not presently clear just what factors contribute to these relations. The goal of the present study was, therefore, to examine the relations between autonomic arousal, neural responsivity, and cognitive performance in the context of a task that required ACC support. Participants completed a primary inhibitory control task with a working memory load embedded. Pre-test cardiovascular measures were obtained, and ontask ERPs associated with response control (N2/P3) and error-related processes (ERN/Pe) were analyzed. Results indicated that response inhibition was unrelated to phasic vagal cardiac control, as indexed by respiratory sinus arrhythmia (RSA). However, higher resting RSA was associated with larger ERN ampUtude for the highest working memory load condition. This finding suggests that those individuals with greater autonomic regulatory control exhibited more robust ACC error-related responses on the most challenging task condition. On the other hand, exploratory analyses with rate pressure product (RPP), a measure of sympathetic arousal, indicated that higher pre-test RPP (i.e., more sympathetic influence) was associated with more errors on "catch" NoGo trials, i.e., NoGo trials that simultaneously followed other NoGo trials, and consequently, reqviired enhanced response control. Higher pre-test RPP was also associated with smaller amplitude ERNs for all three working memory loads and smaller ampUtude P3s for the low and medium working memory load conditions. Thus, higher pretest sympathetic arousal was associated with poorer performance on more demanding "catch" NoGo trials and less robust ACC-related electrocortical responses. The findings firom the present study highlight tiie interdependence of electrocortical and cardiovascular processes. While higher pre-test parasympathetic control seemed to relate to more robust ACC error-related responses, higher pre-test sympathetic arousal resulted in poorer inhibitory control performance and smaller ACC-generated electrocortical responses. Furthermore, these results provide a base from which to explore the relation between ACC and neuro/cardiac responses in older adults who may display greater variance due to the vulnerabihty of these systems to the normal aging process.

Autonomic and electrocortical indices of performance monitoring and source memory discrimination in older and younger adults

Reduced capacity for executive cognitive function and for the autonomic control of cardiac responsivity are both concomitants of the aging process. These may be linked through their mutual dependence on medial prefrontal function, but the specifics ofthat linkage have not been well explored. Executive functions associated with medial prefrontal cortex involve various aspects ofperformance monitoring, whereas centrally mediated autonomic functions can be observed as heart rate variability (HRV), i.e., variability in the length of intervals between heart beats. The focus for this thesis was to examine the degree to which the capacity for phasic autonomic adjustments to heart rate relates to performance monitoring in younger and older adults, using measures of electrocortical and autonomic activity. Behavioural performance and attention allocation during two age-sensitive tasks could be predicted by various aspects of autonomic control. For young adults, greater influence of the parasympathetic system on HRV was beneficial for learning unfamiliar maze paths; for older adults, greater sympathetic influence was detrimental to these functions. Further, these relationships were primarily evoked when the task required the construction and use of internalized representations of mazes rather than passive responses to feedback. When memory for source was required, older adults made three times as many source errors as young adults. However, greater parasympathetic influence on HRV in the older group was conducive to avoiding source errors and to reduced electrocortical responses to irrelevant information. Higher sympathetic predominance, in contrast, was associated with higher rates of source error and greater electrocortical responses tq non-target information in both groups. These relations were not seen for 11 errors associated with a speeded perceptual task, irrespective of its difficulty level. Overall, autonomic modulation of cardiac activity was associated with higher levels of performance monitoring, but differentially across tasks and age groups. With respect to age, those older adults who had maintained higher levels of autonomic cardiac regulation appeared to have also maintained higher levels of executive control over task performance.